This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In contrast to pathogenic lentiviral infections, chronic SIV infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species-specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T lymphocyte apoptosis, immune activation and the SIV-specific cellular immune response in experimentally-infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8-positive T lymphocyte apoptosis temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and interferon-g-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8-positive T lymphocytes despite comparable magnitude of the SIV-specific interferon-gamma ELISPOT response. Furthermore, an increase in CD4-positive and CD4-negativeCD8-negative T lymphocyte apoptosis and plasma TNF-related apoptosis inducing ligand (TRAIL) were only observed in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the "excess" activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and non-natural hosts of SIV infection.